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Urticaria, Angioedema, and Allergic Rhinitis

Chapter 363 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 363

Key Clinical Points

  1. H1 antihistamines are first-line for most urticaria; H2 antagonists and montelukast may be added if inadequate.
  2. Hereditary angioedema (HAE) is bradykinin-mediated and does NOT respond to antihistamines or corticosteroids.
  3. ACE inhibitor-induced angioedema occurs in 0.2–0.7% of patients; risk factors include Black race, female gender, smoking, and increasing age.
  4. Chronic urticaria is defined as attacks persisting for ≥ 6 weeks; acute urticaria is < 6 weeks.
  5. Urticarial lesions last < 24 h and leave no scarring; angioedema lesions last hours to days and may involve the upper airway.
  6. Omalizumab (anti-IgE) is the next line of therapy for chronic urticaria failing first-line options.
  7. C1 inhibitor deficiency (Type 1 or 2) is the hallmark of HAE; C4 and C2 are chronically depleted.
  8. Dermatographism is defined by a linear wheal with surrounding erythema at the site of a brisk stroke.
  9. Cholinergic urticaria presents with small (1–2 mm) pruritic wheals surrounded by a large area of erythema.
  10. Pollen-food syndrome involves oropharyngeal pruritus and/or mild swelling following ingestion of plant-based foods cross-reacting with pollen allergens.

DEFINITION & OVERVIEW

• Urticaria: Definition: Urticaria involves dilation of vascular structures in the superficial dermis. It can occur on any area of the body as well-circumscribed wheals with erythematous raised serpiginous borders and blanched centers that may coalesce to become giant wheals. Urticarial lesions last for < 24 h, are intensely pruritic, frequently migrate around the body, and leave no bruising or scarring. • Angioedema: Definition: Angioedema is marked by dramatic swelling with more pain than pruritus and minimal erythema, which may develop with a pruritic prodrome and takes hours to days to resolve. Angioedema of the upper respiratory tract may be life-threatening due to transient laryngeal obstruction, whereas gastrointestinal involvement may present with abdominal colic, with or without nausea and vomiting, and can result in unnecessary surgical intervention. • General Characteristics: Overlap: Approximately 40% of patients with urticaria also report angioedema. Both conditions affect > 20% of the population at some time during their life span. Scarring: No residual scarring occurs with either urticaria or angioedema unless there is an underlying vasculitic process.

Classification

• Acute vs. Chronic: Acute: Episodes occurring < 6 weeks. Chronic: Episodes occurring ≥ 6 weeks.

EPIDEMIOLOGY

• Prevalence & Demographics: Urticaria/Angioedema: Most common for chronic disease in the third to fifth decades. Women are affected more often than men, with a slight predominance for those with a history of atopy. Acute Cases: More than two-thirds of new-onset urticaria cases are ultimately diagnosed as acute. • Risk Factors: Allergic Rhinitis: Female sex, particulate air pollution exposure, and maternal tobacco smoking. ACE Inhibitor Angioedema: Black race, organ transplant, female gender, smoking, and increasing age.

ETIOLOGY & PATHOPHYSIOLOGY

• General Pathophysiology: Mechanism: Edema of the superficial dermis (urticaria) or subcutaneous tissue/deep dermis (angioedema). Cellular Response: Dilated venules; perivenural infiltrate of lymphocytes, monocytes, eosinophils, and neutrophils. IgE & Mast Cells: Strong evidence for IgE and mast cell involvement in cold urticaria (up to 5% of patients have cryoglobulins or cold agglutinins). Autoimmune Component: Up to 45% of patients with chronic urticaria have an autoimmune cause, including autoantibodies to IgE or to the α chain of Fc\epsilon RI. • Mast Cell Biology: Development: Requires SCF interaction with c-kit. Activation: High-affinity Fc\epsilon RI binds IgE; cross-linking by antigen triggers signaling via Lyn, Syk, and Phospholipase Cγ. Downstream Effects: Mobilization of intracellular calcium → activation of protein kinase C → recruitment of mitogen-activated protein kinases (ERK, JNK, p38) → release of arachidonic acid. • Lipid Mediator Generation: Prostanoid Pathway: Arachidonic acid → Cyclooxygenase → PGH_2. Specific Products: PGD_2 (major mast cell prostanoid) and TXA_2 (causes bronchoconstriction and platelet activation). Leukotriene Pathway: Arachidonic acid → 5-LO & FLAP → 5-HPETE → LTA_4. Branching: LTA_4 can be converted by LTA_4 hydrolase to LTB_4 (mediates neutrophil chemotaxis) or by LTC_4 synthase to LTC_4. Cysteinyl Leukotrienes: LTC_4 is converted by gamma glutamyl transpeptidase and dipeptidase to LTD_4 and LTE_4. Clinical Impact: LTD_4 is a potent bronchoconstrictor; LTE_4 causes vascular leak, recruits eosinophils, and acts on GPR99. Platelet Activating Factor (PAF): Derived from lysophospholipid; levels correlate with severity of anaphylaxis. • Cytokine & Chemokine Production: Cytokines: TNF-α, IL-1, IL-6, IL-4, IL-5, IL-13, and GM-CSF. Chemokines: CCL3, CCL4, CCL8, and CXCL8 (recruit bloodborne leukocytes). • Bradykinin-Mediated Angioedema:* _Mechanism: Bradykinin generation due to C1 inhibitor (C1INH) deficiency or ACE inhibitor use. C1INH Function: C1INH blocks the catalytic function of activated factor XII (Hageman factor), kallikrein, and the C1r/C1s components of C1. C1INH Deficiency Types: Type 1 & 2: Inborn (autosomal dominant) or acquired (autoantibody in malignancy/autoimmune disease). ACE Inhibitor Link: 0.2–0.7% incidence due to delayed degradation of bradykinin. HAE Type 3: Normal C1INH levels; associated with factor XII mutations → excessive bradykinin.

Lipid Mediator Biosynthesis (Flowchart 1)

• Cyclooxygenase Pathway: Arachidonic acid → Cyclooxygenase → PGH_2 → PGD_2 synthase → PGD_2 • 5-lipoxygenase Pathway: Arachidonic acid → (Binding protein [FLAP] & 5-lipoxygenase) → 5-HPETE → LTA_4 synthase → LTA_4 • Cysteinyl Leukotriene Pathway: Arachidonic acid → (via 5-LO pathway) → LTA_4 → LTC_4 synthase → LTC_4 Branching from LTC_4: 1. → Gamma glutamyl transpeptidase and dipeptidase → LTD_4 or LTE_4. 2. → Transport to LTC_4, LTD_4, and LTE_4 receptors. • Alternative Branch: Arachidonic acid → (via 5-LO pathway) → LTA_4 → LTA_4 hydrolase → LTB_4.

CLINICAL FEATURES

• General Urticaria: Presentation: Distinctly pruritic; any body area; 12- to 36-h duration. Morphology: Not symmetric or dependent in distribution. Angioedema: Common sites: periorbital and perioral. Risks: Upper respiratory tract (laryngeal obstruction) → life-threatening; GI involvement → abdominal colic/surgical risk. • Specific Urticaria Types: Dermatographism: Linear wheal with surrounding erythema from firm object stroke; duration < 2h. Pressure Urticaria: Response to sustained stimulus (e.g., strap, belt, running). Cholinergic Urticaria: Small (1–2 mm) pruritic wheals + large area of erythema; triggered by fever, hot bath, or exercise. Exercise-induced anaphylaxis: Potential for progression to angioedema/vascular collapse; may involve IgE specific for α-5 gliadin. Solar Urticaria: Subdivided into 6 groups based on light spectrum. Cold Urticaria: Localized to cold exposure; can progress to vascular collapse in water immersion. Vibratory Urticaria: Often occupational or idiopathic; may be associated with cholinergic urticaria. Other Forms: Local heat, aquagenic (sometimes linked to polycythemia vera), and contact urticaria (e.g., latex). • Allergic Rhinitis:* _Symptoms: Episodic rhinorrhea, sneezing, nasal obstruction, lacrimation, pruritus of conjunctiva/nasal mucosa/oropharynx. Physical Exam: Nasal mucosa pale and boggy; conjunctiva congested/edematous. Pollen-food syndrome: Oropharyngeal pruritus/swelling after eating plants in same family as tree/grass/weed.

DIFFERENTIAL DIAGNOSIS

• Urticarial Vasculitis: Criteria: Lesions > 36 h, resulting in scarring, and reported as painful rather than pruritic. Diagnosis: Biopsy to evaluate for cellular infiltration, nuclear debris, and fibrinoid necrosis of venules. • Mastocytosis: Clinical Clue: Concomitant flushing and hyperpigmented papules that urticate with stroking (in absence of angioedema). • Hereditary Angioedema (HAE): Key Indicators: Lack of pruritus, lack of urticarial lesions, prominent recurrent GI colic, laryngeal edema, and failure to respond to H1 antagonists.

DIAGNOSTIC APPROACH

  1. Initial Assessment: Action: History and physical exam. Laboratory (if unrevealing): CBC (check for eosinophilia), ESR, or CRP.
  2. HAE Specific Diagnosis: Step 1: Assess family history and age of onset. Step 2: Identify lack of pruritus/urticaria and presence of GI colic/laryngeal edema. Step 3: Perform catalytic inhibition assay to detect C1INH antigen (Type 1) or nonfunctional protein (Type 2). Step 4: Measure C4 and C2 levels (chronically depleted in HAE; fall further during attacks). Step 5: For acquired forms, check for reduced C1q protein. Step 6: For Type 3 HAE, identify specific gene mutations (e.g., factor XII).

MANAGEMENT & TREATMENT

  1. Urticaria Treatment: First-line: H1 antihistamines. Second-line (if needed): Add H2 antagonist and/or CysLT receptor antagonist (montelukast). Refractory Cases: Omalizumab: Monoclonal anti-IgE antibody for cases failing first-line. Other Options: Doxepin, cyproheptadine, or hydroxyzine (sedating). Severe/Systemic: Cyclosporine for severe chronic spontaneous urticaria. Note: Topical glucocorticoids are of no value; systemic steroids avoided in most unless specific conditions met.
  2. HAE Management: Clinical Note: HAE does not respond to antihistamines or corticosteroids.
  3. Allergic Rhinitis Management (Flowchart 2): Step 1: Assessment of Duration. If < 4 weeks (Acute): → Exclude medication-induced rhinitis. → Check for anatomic defects/polyps → If present and chronic, refer to ENT. → Perform Allergy evaluation (History, IgE, Asthma). → If Specific Allergen identified (Allergic Rhinitis): Moderate/severe or persistent: Oral/intranasal glucocorticoids + [optional] antihistamines; if severe, consider intranasal steroids. Persistent rhinorrhea: Intranasl ipratropium bromide. → If No specific allergen (Non-allergic Rhinitis): Exclude foreign body/anatomic defect. Treatment: Topical antihistamines and/or glucocorticoids. If no response or moderate/severe: Oral pseudoephedrine or intranasal decongestants. Persistent rhinorrhea: Intranasl ipratropium bromide. If ≥ 4 weeks (Chronic): → Check for infection; if yes, treat as infection (viral or bacterial). → If no infection, check allergic rhinitis history. → If Yes: Treat as allergic rhinitis + intranasal cromolyn (preventive). → If No: Follow Non-allergic Rhinitis path (Topical antihistamines/steroids → if needed, oral pseudoephedrine or decongestants). Special Cases: Uncontrolled symptoms: Immunotherapy (if allergen identified) or omalizumab for asthma/chronic urticaria.

COMPLICATIONS & PROGNOSIS

• Angioedema Risks: Upper Airway: Potential for life-threatening laryngeal obstruction. Gastrointestinal: Abdominal colic, potentially leading to unnecessary surgical intervention.

SPECIAL CONSIDERATIONS

• Hereditary Angioedema (HAE): Clinical Profile: Lack of pruritus/urticaria; prominent GI colic; laryngeal edema. _Laboratory:* C1INH deficiency (Type1 or 2); C4 and C2 are chronically depleted.

KEY PEARLS & CLINICAL TRAPS

• Diagnostic Clues: Urticarial Vasculitis: Look for duration > 36h, pain, and scarring. HAE: Look for lack of pruritus and failure to respond to antihistamines. Cholinergic Urticaria: Small (1-2mm) wheals with large erythema; triggered by heat/exercise. Allergic Rhinitis: Characterized by pale, boggy mucosa and conjunctival edema. • Management Rules:* _H1 Antihistamines: First-line for urticaria. Steroids: Avoid in most urticarias due to toxicity; useful only in specific cases (e.g., pressure urticaria, vasculitic urticaria, or severe allergic rhinitis).

Reference Tables

TABLE 363-1 Classification of Urticaria and/or Angioedema ACUTE Drug reactions

Harrison's 22e, p.2807

ACUTE CHRONIC
Drug reactions
Including (but not limited to):
antimicrobials, nonsteroidal anti-
inflammatory drugs (NSAIDs),
radiocontrast media, opioids,
angiotensin-converting enzyme
(ACE) inhibitors, dipeptidyl
peptidase-4 inhibitors
Vaccine reactions
Food reactions
Inhalation or contact with
environmental allergens
Transfusion reactions
Stinging and biting insects
Toxin (scombroid)
Infections—viral, bacterial, parasitic		 Spontaneous/idiopathic—no
identifiable trigger
Autoimmune—autoimmune component
Physical stimuli (inducible urticaria)
Dermatographism
Cholinergic urticaria
Vibration, cold, pressure, water
(aquagenic)
Sun (solar)
Vascular disease—urticarial vasculitis
and small vessel vasculitis
Mastocytosis (cutaneous or systemic)
Hereditary
Hereditary angioedema (HAE)
C3b inhibitor deficiency
CIAS1-associated periodic fever
syndromes
(familial cold urticaria, Muckle-Wells
syndrome)
Hypereosinophilic syndrome
Schnitzler’s syndrome
Gleich’s syndrome